Cardiovascular diseases are one of the leading causes of death in the world and one of the most significant factors for these diseases is total/high density lipoprotein (HDL) cholesterol level. However, recent developments have indicated that only taking the cholesterol level under control is not sufficient for cardiovascular treatment. In line with this need, researchers have found that the use of some active agents in combination provides a more effective treatment method.
The use of acetylsalicylic acid for reducing the risk of myocardial infarction and the use of statins for lowering cholesterol and preventing or treating cardiovascular disease and cerebrovascular disease are well documented. In fact, it is not uncommon that patients having elevated cholesterol levels who are at high risk for a myocardial infarction take both a statin and acetylsalicylic acid. However, use of both a statin and acetylsalicylic acid may require special care to insure that drug interaction, including physical and chemical incompatibility, and side effects, are kept to a minimum while achieving maximum benefit from these drugs.
HMG-CoA reductase inhibitors can be divided into two groups: those administered as a prodrug, i.e., the lactone form and those administered in the active form, i.e., the acid form or salts of the acid form (e.g. pravastatin sodium, atorvastatin calcium and rosuvastatin calcium). These compounds are unstable since they are susceptible to heat, moisture, low pH environment and light. Both atorvastatin and rosuvastatin and salts thereof, including calcium and magnesium salts, are particularly unstable when compared to other statins. In particular, atorvastatin is transformed into the lactone as a result of the intramolecular esterification reaction. Major degradation products (3R, 5S) produced as a result of disintegration of statins are lactones and oxidation products. This fact reduces the stability of atorvastatin and therefore shortens its shelf life.
It is known from the prior art that HMG-CoA reductase inhibitors degrade in the presence of acetylsalicylic acid during storage.
Document WO9738694 discloses pharmaceutical compositions comprising aspirin and a statin. However, the problem of statin-aspirin interaction is not addressed. Document EP1071403 addresses the problem of said interaction and describes a formulation in the form of a bilayered tablet. Aspirin, in the form of granules, is present in the first layer while the statin is present in the second layer. However, combination products produced in bilayer dosage forms can fail to prevent interaction of the active agents with each other. In this case, the product may be degraded during its shelf life. This may result in serious complications to the patient and insufficient dose intake.
Document EP 1581194 relates to multilayer tablet dosage form comprising pravastatin and aspirin as active agents. The layers comprising the active agents are separated by a barrier layer in order to impede their interaction. However, it is quite inconvenient to produce this type of tablet formulations and it is not certainly known if the barrier layer would maintain its effect during the shelf life.
Document WO2011096665 describes that the deterioration in the stability of HMG-CoA reductase can be prevented by coating aspirin with a barrier containing a hydrophobic additive. According to said document, when aspirin is coated with conventional coatings, HMG-CoA reductase inhibitors are degraded. When a hydrophobic additive is added to the coating layer, the degradation of HMG-CoA reductase inhibitors is reduced.
In view of the above, it is seen that there is a need in patients required to take both a statin and acetylsalicylic acid for a statin-acetylsalicylic acid formulation which provides for maximum effect in cardiovascular diseases prevention and treatment without the undesirable side effects and drug interaction normally associated with use of such combination.
In accordance with the present invention, a pharmaceutical composition is provided which includes a HMG-CoA reductase inhibitor selected from atorvastatin and rosuvastatin and salts thereof, and acetylsalicylic acid, which provides for maximum patient benefits with minimal physical and chemical incompatibility and reduced side effects normally associated with use of such drugs.